Mogrosides are a class of tetracyclic triterpenoid saponins found predominantly in Siraitia grosvenorii (Luo Han Guo), a fruit widely used in traditional Chinese medicine. In this study, an efficient and rapid detection method was developed to detect 17 kinds of mogrosides in S. grosvenorii using ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry (UPLC-MS/MS) combined with targeted metabolomics and their variations during fruit development. The results demonstrated that the 17 mogrosides exhibited good linearity (R>0.990) within their detection ranges, with the average spiked recovery rate exceeding 95%. In the different linear ranges of the mogrosides, detection limits were between 0.047 and 3.834 μg/L, while quantitation limits were between 0.158 and 12.780 μg/L. At the early fruit growth stage (15 to 30 d) of S. grosvenorii, mogroside IIe was the predominant mogroside that continued to accumulate. At the middle growth stage (30 to 50 d), mogroside III and other mogrosides gradually accumulated. As the fruit continued to grow, these mogrosides transformed into various compounds, such as siamenoside I. At 50 to 70 d, compounds such as siamenoside I glycosylated to generate mogrosides, including mogroside V. In the final growth stage (70 to 90 d), saponin accummulation mainly consisted of mogroside V, generated through glycosylation, which reached its peak and then stabilized. The proposed method offers an ideal approach for qualitative and quantitative analysis of multiple isomers of mogrosides in S. grosvenorii samples, providing high sensitivity and accuracy.